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filters.cpp
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//////////////////////////////////////////////////////////////////
// //
// PLINK (c) 2005-2008 Shaun Purcell //
// //
// This file is distributed under the GNU General Public //
// License, Version 2. Please see the file COPYING for more //
// details //
// //
//////////////////////////////////////////////////////////////////
#include <iostream>
#include <iomanip>
#include <fstream>
#include <sstream>
#include <vector>
#include <map>
#include <cmath>
#include <iterator>
#include "plink.h"
#include "options.h"
#include "helper.h"
#include "stats.h"
#include "crandom.h"
#define MISSING(i,l) ( SNP[l]->one[i] && ( ! SNP[l]->two[i] ) )
void Plink::filterSNPs()
{
//////////////////////////////////////////////////////
// This functions applies the following filters and
// functions:
// Counts of number of founders, nonfounders
// Per-individual genotyping rate
// Read in, or calculate, allele frequencies (and save these)
// Optionally write allele frequencies, then close
// Exclude SNPs with too many missing genotypes
// Identify/correct heterozygote haploid
// Identify SNPs with no founder genotypes
// Calculate/report/filter on HWE tests
// Calculate/report genotyping rate per SNP/per individual
// Filter on MAF
// Remove filtered-out SNPs
bool original_SNP_major = par::SNP_major;
if ( ! par::SNP_major )
Ind2SNP();
// Which SNPs to delete
vector<bool> del(locus.size(),false);
// Which individuals to delete
vector<bool> indel(sample.size(),false);
//////////////////////////////////////////
// Display number of founders/nonfounders
cnt_f=0;
vector<Individual*>::iterator person = sample.begin();
while ( person != sample.end() )
{
if ( (*person)->founder ) cnt_f++;
person++;
}
printLOG(int2str(cnt_f)+" founders and "+int2str(n-cnt_f)+
" non-founders found\n");
if (cnt_f<n) par::has_nonfounders = true;
////////////////////////////////////////////
// If we have obligatory missing genotypes:
// ensure they really are missng
if ( par::oblig_missing )
{
set<int2>::iterator p = oblig_missing.begin();
while ( p != oblig_missing.end() )
{
int l = p->p1;
int k = p->p2;
for (int i=0; i<sample.size(); i++)
{
Individual * person = sample[i];
if ( person->sol == k )
{
SNP[l]->one[i] = true;
SNP[l]->two[i] = false;
}
}
++p;
}
}
/////////////////////////////////////////////////
// Remove individuals with too many missing calls
double total_genotyping = 0;
if ( par::MAX_IND_MISSING < 1 )
{
int n_removed = 0;
int n_orig = n;
// Consider each individual
if ( ! par::oblig_missing )
{
for (int i=0;i<sample.size();i++)
{
bool female = !sample[i]->sex;
// Sum missingness over all SNPs
int m=0; // Missing SNPs
int nsnps=0; // All non-obligatory missing SNPs
for (int l=0; l<locus.size();l++)
{
// Skip female Y chromosomes
if ( female && par::chr_Y[locus[l]->chr] )
{
continue;
}
++nsnps;
if ( MISSING(i,l) ) m++;
}
// Too much missingness?
if ( (double)m/(double)nsnps > par::MAX_IND_MISSING )
{
indel[i] = true;
n_removed++;
}
} // next individual
}
else // ... allow oblig missing values
{
for (int i=0;i<sample.size();i++)
{
bool female = ! sample[i]->sex;
// Sum missingness over all SNPs
int m=0; // Missing SNPs
int nsnps=0; // All non-obligatory missing SNPs
for (int l=0; l<locus.size();l++)
{
// Skip female Y chromosomes
if ( female && par::chr_Y[locus[l]->chr] )
continue;
if ( ! obligMissing(i,l) )
{
if ( MISSING(i,l) )
++m;
++nsnps;
}
}
// Too much missingness?
if ( (double)m/(double)nsnps > par::MAX_IND_MISSING )
{
indel[i] = true;
n_removed++;
}
} // next individual
} // end if oblig-missing section
////////////////////////////////////////
// Save list of any removed individuals
if (n_removed>0)
{
string f = par::output_file_name + ".irem";
printLOG("Writing list of removed individuals to [ " + f + " ]\n");
ofstream REM;
REM.open(f.c_str(), ifstream::out);
for (int i=0;i<sample.size();i++)
if (indel[i])
REM << sample[i]->fid << "\t" << sample[i]->iid << "\n";
REM.close();
// And now remove these individuals, so that
// SNP-based statistics are calculated with
// these samples already excluded
n_removed = deleteIndividuals(indel);
}
printLOG(int2str(n_removed)+" of "+int2str(n_orig));
printLOG(" individuals removed for low genotyping ( MIND > ");
printLOG(dbl2str(par::MAX_IND_MISSING)+" )\n");
} // end of remove people conditional
/////////////////////////////////
// Calculate or read from file?
if (par::af_read)
{
checkFileExists(par::af_file);
printLOG( "Reading allele frequencies from [ " + par::af_file + " ] \n");
// Make hash of original SNP names
map<string,int> mlocus;
map<string,int>::iterator ilocus;
vector<Locus*>::iterator loc = locus.begin();
int l=0;
while ( loc != locus.end() )
{
mlocus.insert(make_pair( (*loc)->name,l));
loc++;
l++;
}
// Read allele frequencies
ifstream FRQ;
FRQ.open(par::af_file.c_str());
FRQ.clear();
string dum1, dum2, dum3, dum4, dum5, dum6;
string snpname;
double freq;
int nm;
loc = locus.begin();
while ( loc != locus.end() )
{
(*loc)->freq = -1;
(*loc)->nm = 0;
loc++;
}
// Skip header line
FRQ >> dum1 >> dum2 >> dum3 >> dum4 >> dum5 >> dum6;
while(!FRQ.eof())
{
vector<string> tokens = tokenizeLine(FRQ);
if (tokens.size() == 0)
continue;
else if (tokens.size() != 6)
{
string sline="";
for (int i=0; i<tokens.size(); i++)
sline += tokens[i] + " ";
error("Problem with allele frequency line: 6 fields required:\n"
+sline+"\n");
}
ilocus = mlocus.find(tokens[1]);
if (ilocus != mlocus.end())
{
string rareAllele = tokens[2];
string commonAllele = tokens[3];
Locus * loc = locus[ilocus->second];
if( ! from_string<double>( loc->freq, tokens[4],std::dec))
{
loc->freq = 0;
loc->nm = 0;
}
else if( ! from_string<int>(loc->nm,tokens[5],std::dec))
{
loc->freq = 0;
loc->nm = 0;
}
// But was that pointing to the correct allele?
if ( rareAllele == loc->allele2 &&
rareAllele != par::missing_genotype &&
loc->allele2 != par::missing_genotype )
loc->freq = 1 - loc->freq;
else if ( commonAllele == loc->allele1 &&
commonAllele != par::missing_genotype &&
loc->allele1 != par::missing_genotype )
loc->freq = 1 - loc->freq;
}
}
FRQ.clear();
FRQ.close();
}
/////////////////////////////////
// Calculate allele frequencies
vector<string> hetlist(0);
vector<bool>::iterator d = del.begin();
vector<Locus*>::iterator loc = locus.begin();
vector<CSNP*>::iterator s = SNP.begin();
int l = 0; // Main locus counter
int exc_maf = 0;
int exc_miss = 0;
vector<Locus*> no_founders_found_list;
while ( loc != locus.end() )
{
if (!par::af_read)
{
(*loc)->freq = 0;
// count 1 per allele, for frequency
(*loc)->nm = 0;
}
// count 1 per genotype, for missingness
int geno_nm = 0;
// count 1 per non-obligatory missing genotype
// (or set to N individuals)
int geno_real = 0;
bool X = false;
bool haploid = false;
// Determine type of SNP
if (par::chr_sex[(*loc)->chr]) X=true;
else if (par::chr_haploid[(*loc)->chr]) haploid=true;
///////////////////////////////
// Iterate over each individual
vector<bool>::iterator i1 = (*s)->one.begin();
vector<bool>::iterator i2 = (*s)->two.begin();
vector<Individual*>::iterator person = sample.begin();
int i = 0;
while ( person != sample.end() )
{
bool s1 = *i1;
bool s2 = *i2;
// Check female Y genotypes
if ( par::chr_Y[(*loc)->chr] && ! (*person)->sex )
{
// Set to missing, unless in a RECODE mode
if ( ! par::preserve_all_genotypes )
{
s1 = *i1 = true;
s2 = *i2 = false;
}
// But in any case, do not include this marker in
// any genotype counts: skip to next person
++person;
++i;
++i1;
++i2;
continue;
}
// For haploid heterozygosity check, also consider all individuals
if ( haploid || ( X && (*person)->sex ) )
{
if ( (!s1) && s2 )
{
hetlist.push_back( (*person)->fid + "\t" +
(*person)->iid + "\t" +
(*loc)->name );
// Set to missing, unless in a RECODE mode
if ( ! par::preserve_all_genotypes )
{
s1 = *i1 = true;
s2 = *i2 = false;
}
}
}
// For missing genotypes
if ( ! ( s1 && (!s2) ) )
geno_nm++;
// But is this a real genotype in any case?
if ( par::oblig_missing )
{
if ( ! obligMissing(i,l) )
++geno_real;
}
else
++geno_real;
// Do not recount alleles if we have read in allele frequencies
if (!par::af_read)
{
// For allele frequencies
// only consider founders
if ( par::summ_nonfounders || (*person)->founder )
{
if ( haploid || ( X && (*person)->sex ) )
{
//////////////////
// Haploid counts
// "1" allele count
if ( (!s1) && (!s2) ) // FF = hom(11)
{
(*loc)->freq++;
(*loc)->nm++;
}
else if ( s1 && s2 ) // TT = hom(22)
{
(*loc)->nm++;
}
}
else
{
//////////////////
// Autosomal count
// "1" allele count
if (!s1)
{
if (!s2) // 00 = hom(11)
{
(*loc)->freq+=2;
(*loc)->nm+=2;
}
else // 01 = het(12)
{
(*loc)->freq+=1;
(*loc)->nm+=2;
}
}
else if ( s2 ) // 11 = hom(22)
{
(*loc)->nm+=2;
}
}
}
}
// Next individual
++person;
++i;
++i1;
++i2;
}
////////////////////////////////
// Calculate allele frequencies
if (!par::af_read)
{
if ( par::af_count) // Allele counts...
{
// Use freq to store count (keep as is)
// Use "bp" to store number of allele 2
(*loc)->bp = (long int)((*loc)->nm - (*loc)->freq);
// Use "pos" to store number missing genotypes
(*loc)->pos = geno_real - geno_nm;
}
else // ... or frequencies
{
if ((*loc)->nm>0)
(*loc)->freq /= (double)(*loc)->nm;
else
{
(*loc)->freq = 1;
// If we aren't getting rid of it anyway
if ( (double)geno_nm/(double)geno_real >= (1-par::MAX_GENO_MISSING))
no_founders_found_list.push_back(*loc);
}
}
}
//////////////////////////////////////////
// Record total proportion of missingness
double snp_genotyping = n>0 ? (double)geno_nm/(double)geno_real : 0;
total_genotyping += snp_genotyping;
/////////////////////////////////////////////////
// Exclude if SNP has too many missing genotypes
if ( snp_genotyping < (1-par::MAX_GENO_MISSING) )
{
*d = true;
exc_miss++;
}
////////////////////////////////////////////////
// Make allele1 always the least common allele
if ( par::make_minor_allele && (!par::af_count) && (*loc)->freq > 0.5 )
{
// then we need to swap alleles
(*loc)->freq = 1 - (*loc)->freq;
string tmp = (*loc)->allele2;
(*loc)->allele2 = (*loc)->allele1;
(*loc)->allele1 = tmp;
vector<bool>::iterator i1 = (*s)->one.begin();
vector<bool>::iterator i2 = (*s)->two.begin();
while ( i1 != (*s)->one.end() )
{
if ( (*i1) == (*i2) )
{
*i1 = ! (*i1);
*i2 = ! (*i2);
}
i1++;
i2++;
}
}
// Next SNP
++d;
++loc;
++l;
++s;
}
/////////////////////////////////////////////////
// Save list of any heterozygous haploid alleles
if (hetlist.size()>0)
{
printLOG(int2str( hetlist.size())
+ " heterozygous haploid genotypes; set to missing\n");
string f = par::output_file_name + ".hh";
printLOG("Writing list of heterozygous haploid genotypes to [ "
+ f + " ]\n");
ofstream REM;
REM.open(f.c_str(), ifstream::out);
for (int i=0; i<hetlist.size(); i++)
REM << hetlist[i] << "\n";
REM.close();
}
hetlist.clear();
/////////////////////////////////////////////////
// Save list of SNPs with no founders observed
if (no_founders_found_list.size()>0)
{
printLOG(int2str( no_founders_found_list.size())
+ " SNPs with no founder genotypes observed\n");
printLOG("Warning, MAF set to 0 for these SNPs (see --nonfounders)\n");
string f = par::output_file_name + ".nof";
printLOG( "Writing list of these SNPs to [ " + f + " ]\n");
ofstream NOF;
NOF.open(f.c_str(), ifstream::out);
for (int i=0; i<no_founders_found_list.size(); i++)
NOF << no_founders_found_list[i]->name << "\n";
NOF.close();
}
no_founders_found_list.clear();
//////////////////////////
// Write allele freq file
if (par::af_write)
{
if (par::include_cluster_from_file)
calcStratifiedAlleleFreqs();
else
{
ofstream FRQ;
string f = par::output_file_name + ".frq";
if (par::af_count) f += ".count";
if (par::summ_nonfounders)
printLOG("Writing allele frequencies (all individuals) to [ "
+ f + " ] \n");
else
printLOG("Writing allele frequencies (founders-only) to [ "
+ f + " ] \n");
if (par::af_count)
printLOG("Display counts rather than frequencies\n");
FRQ.open(f.c_str(), ifstream::out);
FRQ.precision(4);
FRQ << setw(4) << "CHR" << " "
<< setw(par::pp_maxsnp) << "SNP" << " "
<< setw(4) << "A1" << " "
<< setw(4) << "A2" << " ";
if (par::af_count)
FRQ << setw(6) << "C1" << " "
<< setw(6) << "C2" << " "
<< setw(6) << "G0" << "\n";
else
FRQ << setw(12) << "MAF" << " "
<< setw(8) << "NCHROBS"
<< "\n";
vector<Locus*>::iterator loc = locus.begin();
while (loc != locus.end() )
{
string a1 = (*loc)->allele1;
string a2 = (*loc)->allele2;
if (a1=="") a1="0";
if (a2=="") a2="0";
FRQ << setw(4) << (*loc)->chr << " "
<< setw(par::pp_maxsnp) << (*loc)->name << " "
<< setw(4) << a1 << " "
<< setw(4) << a2 << " ";
if (par::af_count)
{
FRQ << setw(6) << int( (*loc)->freq ) << " "
<< setw(6) << int( (*loc)->bp ) << " "
<< setw(6) << int( (*loc)->pos ) << "\n";
}
else
{
if ( (*loc)->nm > 0 )
FRQ << setw(12) << (*loc)->freq << " ";
else
FRQ << setw(12) << "NA" << " ";
FRQ << setw(8) << (*loc)->nm << "\n";
}
loc++;
}
FRQ.close();
}
// Close after we've done alle freqs,
shutdown();
}
/////////////////////////
// Write HWE statistics
if (par::HWD_test || par::HWD_report)
{
ofstream HWD;
if (par::HWD_report)
{
if (par::summ_nonfounders)
printLOG("Writing Hardy-Weinberg tests (all individuals) to [ " +
par::output_file_name + ".hwe ] \n");
else
printLOG("Writing Hardy-Weinberg tests (founders-only) to [ " +
par::output_file_name + ".hwe ] \n");
string f = par::output_file_name + ".hwe";
HWD.open(f.c_str(), ifstream::out);
HWD.precision(4);
HWD << setw(4) << "CHR" << " "
<< setw(par::pp_maxsnp) << "SNP" << " "
<< setw(8) << "TEST" << " "
<< setw(4) << "A1" << " "
<< setw(4) << "A2" << " "
<< setw(20) << "GENO" << " "
<< setw(8) << "O(HET)" << " "
<< setw(8) << "E(HET)" << " "
<< setw(12) << "P" << " "
<< "\n";
}
int cnt=0, cnt_a=0, cnt_u=0;
////////////////////////
// Consider each locus
vector<bool>::iterator d = del.begin();
vector<Locus*>::iterator loc = locus.begin();
for ( int l = 0 ; l < locus.size() ; l++ )
{
// Compute p-values for HWE test in cases, controls & all
// Only consider founders
int a11, a12, a22;
int u11, u12, u22;
int b11, b12, b22;
a11=a12=a22=0;
u11=u12=u22=0;
b11=b12=b22=0;
bool X = false, haploid = false;
if (par::chr_sex[(*loc)->chr]) X=true;
else if (par::chr_haploid[(*loc)->chr]) haploid=true;
///////////////////////////////////////////////
// Iterate over each individual, founders only
for ( int i = 0 ; i < sample.size() ; i++ )
{
Individual * person = sample[i];
///////////////////////////////////////////////
// Only consider founders, & diploid genotypes
if ( par::summ_nonfounders || person->founder )
if ( ! ( haploid || ( X && person->sex ) ) )
{
bool s1 = SNP[l]->one[i];
bool s2 = SNP[l]->two[i];
// Consider everybody, irrespective of phenotype
// (QT, C/C or missing)
if (!s1)
{
if (!s2) b11++; // 00 = hom(11)
else b12++; // 01 = het(12)
}
else if ( s2 ) b22++; // 11 = hom(22)
if (par::bt) // for binary trait, separately for cases/controls
{
if (person->phenotype == 1)
{
if (!s1)
{
if (!s2) u11++; // 00 = hom(11)
else u12++; // 01 = het(12)
}
else if ( s2 ) u22++; // 11 = hom(22)
}
else if (person->phenotype == 2)
{
if (!s1)
{
if (!s2) a11++; // 00 = hom(11)
else a12++; // 01 = het(12)
}
else if ( s2 ) a22++; // 11 = hom(22)
}
}
}
// Next individual
}
// Allele frequencies
double afreq = 0, ufreq = 0, freq = 0;
bool include_cases = true;
bool include_controls = true;
if (par::qt)
freq = ( b11 + (double)b12/2.0 ) / (double)( b11+b12+b22 );
else
{
afreq = ( a11 + (double)a12/2.0 ) / (double)( a11+a12+a22 );
ufreq = ( u11 + (double)u12/2.0 ) / (double)( u11+u12+u22 );
freq = ( b11 + (double)b12/2.0 ) / (double)( b11+b12+b22 );
if ( a11+a12+a22 == 0 ) include_cases = false;
if ( u11+u12+u22 == 0 ) include_controls = false;
}
if (par::qt)
{
double p;
if (par::HWD_standard)
{
double tot = b11 + b12 + b22;
double exp_11 = freq * freq * tot;
double exp_12 = 2 * freq * (1-freq) * tot;
double exp_22 = (1-freq) * (1-freq) * tot;
double chisq = ( (b11-exp_11)*(b11-exp_11) ) / exp_11
+ ( (b12-exp_12)*(b12-exp_12) ) / exp_12
+ ( (b22-exp_22)*(b22-exp_22) ) / exp_22 ;
p = chiprobP(chisq,1);
}
else
p = SNPHWE( b12, b11, b22 );
if (par::HWD_report)
{
HWD << setw(4) << (*loc)->chr << " "
<< setw(par::pp_maxsnp) << (*loc)->name << " "
<< setw(8) << "ALL(QT)" << " "
<< setw(4) << (*loc)->allele1 << " "
<< setw(4) << (*loc)->allele2 << " "
<< setw(20) << (int2str(b11)+
"/"+int2str(b12)+
"/"+int2str(b22)) << " "
<< setw(8) << (double)b12/(double)(b11+b12+b22) << " "
<< setw(8) << 2 * freq * (1-freq) << " ";
if ( realnum(p) )
HWD << setw(12) << p << "\n";
else
HWD << setw(12) << "NA" << "\n";
}
if ( p <= par::HWD_limit && p > -1 )
{
cnt++;
*d = true;
}
}
else
{
// For case/control data
double p, p_a, p_u;
if (par::HWD_standard)
{
double exp_a11 = afreq * afreq * (a11+a12+a22);
double exp_a12 = 2 * afreq * (1-afreq) * (a11+a12+a22);
double exp_a22 = (1-afreq) * (1-afreq) * (a11+a12+a22);
double exp_u11 = ufreq * ufreq * (u11+u12+u22);
double exp_u12 = 2 * ufreq * (1-ufreq) * (u11+u12+u22);
double exp_u22 = (1-ufreq) * (1-ufreq) * (u11+u12+u22);
double exp_11 = freq * freq * (b11+b12+b22);
double exp_12 = 2 * freq * (1-freq) * (b11+b12+b22);
double exp_22 = (1-freq) * (1-freq) * (b11+b12+b22);
double chisq_a = ( (a11-exp_a11)*(a11-exp_a11) ) / exp_a11
+ ( (a12-exp_a12)*(a12-exp_a12) ) / exp_a12
+ ( (a22-exp_a22)*(a22-exp_a22) ) / exp_a22 ;
double chisq_u = ( (u11-exp_u11)*(u11-exp_u11) ) / exp_u11
+ ( (u12-exp_u12)*(u12-exp_u12) ) / exp_u12
+ ( (u22-exp_u22)*(u22-exp_u22) ) / exp_u22 ;
double chisq = ( (b11-exp_11)*(b11-exp_11) ) / exp_11
+ ( (b12-exp_12)*(b12-exp_12) ) / exp_12
+ ( (b22-exp_22)*(b22-exp_22) ) / exp_22 ;
p = chiprobP(chisq,1);
p_a = chiprobP(chisq_a,1);
p_u = chiprobP(chisq_u,1);
}
else
{
p = SNPHWE( b12, b11, b22 );
p_a = SNPHWE( a12, a11, a22 );
p_u = SNPHWE( u12, u11, u22 );
}
if (par::HWD_report)
{
HWD << setw(4) << (*loc)->chr << " "
<< setw(par::pp_maxsnp) << (*loc)->name << " "
<< setw(8) << "ALL" << " "
<< setw(4) << (*loc)->allele1 << " "
<< setw(4) << (*loc)->allele2 << " "
<< setw(20)
<< int2str(b11)+"/"+int2str(b12)+"/"+int2str(b22) << " "
<< setw(8) << (double)b12/(double)(b11+b12+b22) << " "
<< setw(8) << 2 * freq * (1-freq) << " ";
if ( p > -1 )
HWD << setw(12) << p << "\n";
else
HWD << setw(12) << "NA" << "\n";
HWD << setw(4) << (*loc)->chr << " "
<< setw(par::pp_maxsnp) << (*loc)->name << " "
<< setw(8) << "AFF" << " "
<< setw(4) << (*loc)->allele1 << " "
<< setw(4) << (*loc)->allele2 << " "
<< setw(20)
<< int2str(a11)+"/"+int2str(a12)+"/"+int2str(a22) << " "
<< setw(8) << (double)a12/(double)(a11+a12+a22) << " "
<< setw(8) << 2 * afreq * (1-afreq) << " ";
if (include_cases && p_a > -1 )
HWD << setw(12) << p_a << "\n";
else
HWD << setw(12) << "NA" << "\n";
HWD << setw(4) << (*loc)->chr << " "
<< setw(par::pp_maxsnp) << (*loc)->name << " "
<< setw(8) << "UNAFF" << " "
<< setw(4) << (*loc)->allele1 << " "
<< setw(4) << (*loc)->allele2 << " "
<< setw(20)
<< int2str(u11)+"/"+int2str(u12)+"/"+int2str(u22) << " "
<< setw(8) << (double)u12/(double)(u11+u12+u22) << " "
<< setw(8) << 2 * ufreq * (1-ufreq) << " ";
if (include_controls && p_u > -1 )
HWD << setw(12) << p_u << "\n";
else
HWD << setw(12) << "NA" << "\n";
}
// Increase counts: in cases
if ( include_cases && p_a < par::HWD_limit && p_a > -1 ) cnt_a++;
// Controls (and, if possible, exclude on this value)
if ( include_controls &&
p_u < par::HWD_limit && p_u > -1 )
{
cnt_u++;
if ( ! par::HWD_filter_on_all )
{
*d = true;
cnt++;
}
}
// In total sample, and if needed, exclude here
if ( p < par::HWD_limit && p>-1 )
{
if ( par::HWD_filter_on_all || ! include_controls )
{
*d = true;
cnt++;